1. Field of the Invention
The present invention relates generally to methods and compounds for treating pulmonary disorders, and more specifically to the use of hIL-4 mutant proteins to treat asthma.
2. Background Information
Interleukin-4 (IL-4) and Interleukin-13 (IL-13) are pleiotropic cytokines with a broad spectrum of biological effects on several target cells important in the pathogenesis of atopy and asthma. IL-4 is increasingly appreciated as the pivotal cytokine initiating the “Th2-type” inflammatory response forming the underling milieu necessary for the development of atopy and asthma. IL-4 effects include activation, proliferation and differentiation of T and B cells. During proliferation of B-lymphocytes, IL-4 acts as a differentiation factor by regulating class switching from IgG to IgE thus, encouraging the development of allergic reactions. IL-13 is now appreciated as the more probable downstream effector cytokine. IL-13 dominant effects include induction of airways hyperresponsiveness (AHR) and goblet cell hyperplasia, both cardinal features of asthma. However, there is considerable redundancy in the effects of these two cytokines.
The redundancy in effects associated with the binding and signaling of these two cytokines can be explained by their sharing of common receptors. The IL-4 receptor alpha chain (IL-4Rα) has two binding partners with which it can associate and signal. IL-4Rα polypeptide associates with the cytokine common receptor gamma chain (γc) to form the type 1 IL-4R receptor heterodimer. IL-4Rα polypeptide can also form a heterodimer with the IL-13 receptor alpha 1 chain to create the type 2 IL-4R (aka IL-13R). IL-4 activates both the type 1 and type 2 receptors whereas IL-13 only activates the type 2 receptor heterodimer. Both receptors, when activated, signal through the transcription factor signal transducer and activator of transcription 6 (STAT6). Although IL-4 may uniquely initiate the T-helper 2 (Th2) pathway, since only type 1 receptors are localized to T lymphocytes, IL-13 may be both more abundant and more potent. Thus inhibition of both cytokines is important in disease states regulated and controlled by the production of these two cytokines.
Recently, certain antagonistic and partially antagonistic properties have been observed in human IL-4 (hIL-4) mutant proteins in which the amino acid(s) occurring naturally in the wild type at one or more of positions 120, 121, 122, 123, 124, 125, 126, 127 or 128 have been replaced with one or more natural amino acids. Thus, these hIL-4 muteins have been described as valuable therapeutic agents for use as medicaments in treating overshooting or falsely regulated immune reactions and autoimmune diseases.